Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma

Abstract

Single nucleotide polymorphisms (SNPs) close to the gain-of-function substitution, Asn(107)Ile (rs324981, A>T), in Neuropeptide S Receptor 1 (NPSR1) have been associated with asthma. Furthermore, a functional SNP (rs4751440, G>C) in Neuropeptide S (NPS) encodes a Val(6)Leu substitution on the mature peptide that results in reduced bioactivity. We sought to examine the effects of different combinations of these NPS and NPSR1 variants on downstream signaling and genetic risk of asthma. In transfected cells, the magnitude of NPSR1-induced activation of cAMP/PKA signal transduction pathways and downstream gene expression was dependent on the combination of the NPS and NPSR1 variants with NPS-Val(6)/NPSR1-Ile(107) resulting in strongest and NPS-Leu(6)/NPSR1-Asn(107) in weakest effects, respectively. One or two copies of the NPS-Leu(6) (rs4751440) were associated with physician-diagnosed childhood asthma (OR: 0.67, 95%CI 0.49–0.92, p = 0.01) and together with two other linked NPS variants (rs1931704 and rs10830123) formed a protective haplotype (p = 0.008) in the Swedish birth cohort BAMSE (2033 children). NPS rs10830123 showed epistasis with NPSR1 rs324981 encoding Asn(107)Ile (p = 0.009) in BAMSE and with the linked NPSR1 rs17199659 (p = 0.005) in the German MAGIC/ISAAC II cohort (1454 children). In conclusion, NPS variants modify asthma risk and should be considered in genetic association studies of NPSR1 with asthma and other complex diseases.

Uncovering new disease indications for G-protein coupled receptors and their endogenous ligands

“…Neuropeptide S receptor 1 (NPSR1) was identified as a potential new drug target for asthma in the Open Targets platform. Strong genetic evidence supports the hypothesis [ 41 – 43 ] and the Open Targets platform identifies over 60 publications suggesting a role of NPSR1 in asthma but the exact mechanism of NPSR1 in the disease remains elusive. Although increased NPSR1 protein levels in plasma were reported in asthma [ 44 ] and increased NPSR1 mRNA expression was observed in eosinophils from severe asthmatic patients [ 45 ], experiments in an experimental asthma mouse model showed no impact of Npsr1 deletion on airway inflammation or hyper-responsiveness, and the authors suggested that NPSR1 affects the disease through a central nervous system-mediated pathway [ 46 ].…”

Selection in the Finnhorse, a native all‐around horse breed

“…We found F ST outliers in regions close to genes associated with immune system and IgE, for example STAT1 and STAT2 ( signal transducer and activator of transcription ) genes, IL23A ( interleukin 23, alpha subunit p19 ), CLEC5A ( C‐type lectin domain containing 5A ) and NPSR1 ( neuropeptide S receptor 1 ; Table S2). STAT genes are present in several homologues in the genome, and in humans, defects, for example in STAT3 gene, have been connected with hyper‐IgE syndrome and atopic dermatitis (Boos et al., 2014; Shuai & Liu, 2003) and NPSR1 has been proposed to be involved in IgE‐mediated diseases in humans, such as allergic eczema and asthma (Acevedo et al., 2017). CLEC5A has been connected with innate immunity against several pathogens (Chen et al., 2017) and IL23A with inflammation, immune response and cell differentiation and survival (Brocker et al., 2010).…”

Pharmacology, Physiology and Genetics of the Neuropeptide S System

“…NPSR1 was one of the candidate genes and was termed GPRA (G protein-coupled receptor for asthma susceptibility) [ 35 ]. Further studies have reported genetic linkage of the NPSR1 locus on human Chr7 with inflammatory or allergic disorders, including asthma, airway hyper-responsiveness, atopic dermatitis, inflammatory bowel syndrome, and rheumatoid arthritis [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ], although some studies failed to replicate such associations [ 95 , 96 , 97 , 98 ]. Complex haplotypes in and surrounding the NPSR1 gene, rather than individual single nucleotide polymorphisms (SNPs), were identified in these association studies and a detailed physiological mechanism has not yet been described to explain NPSR1-related functions in allergic or inflammatory diseases.…”

“…A mutation reducing agonist potency 10–20 fold has been identified in the NPS peptide itself, producing Leu 6 -NPS (instead of Val 6 ; rs4751440, G/C) [ 94 , 116 ]. Thus far, no phenotypes have been associated with this variant, which might be due to the relatively low allele frequency and geographically restricted occurrence in European and Indian populations.…”